Outcomes after distal pancreatectomy with or without splenectomy for intraductal papillary mucinous neoplasm: international multicentre cohort study

Abstract Background International guidelines on intraductal papillary mucinous neoplasm (IPMN) recommend a formal oncological resection including splenectomy when distal pancreatectomy is indicated. This study aimed to compare oncological and surgical outcomes after distal pancreatectomy with or without splenectomy in patients with presumed IPMN. Methods An international, retrospective cohort study was undertaken in 14 high-volume centres from 7 countries including consecutive patients after distal pancreatectomy for IPMN (2005–2019). Patients were divided into spleen-preserving distal pancreatectomy (SPDP) and distal pancreatectomy with splenectomy (DPS). The primary outcome was lymph node metastasis (LNM). Secondary outcomes were overall survival, duration of operation, blood loss, and secondary splenectomy. Results Overall, 700 patients were included after distal pancreatectomy for IPMN; 123 underwent SPDP (17.6%) and 577 DPS (82.4%). The rate of malignancy was 29.6% (137 patients) and the overall rate of LNM 6.7% (47 patients). Patients with preoperative suspicion of malignancy had a LNM rate of 17.2% (23 of 134) versus 4.3% (23 of 539) among patients without suspected malignancy (P < 0.001). Overall, SPDP was associated with a shorter operating time (median 180 versus 226 min; P = 0.001), less blood loss (100 versus 336 ml; P = 0.001), and shorter hospital stay (5 versus 8 days; P < 0.001). No significant difference in overall survival was observed between SPDP and DPS for IPMN after correction for prognostic factors (HR 0.50, 95% c.i. 0.22 to 1.18; P = 0.504). Conclusion This international cohort study found LNM in 6.7% of patients undergoing distal pancreatectomy for IPMN. In patients without preoperative suspicion of malignancy, SPDP seemed oncologically safe and was associated with improved short-term outcomes compared with DPS.


Introduction
Pancreatic cystic neoplasms are being detected at an increasing rate because of the expanding use of high-quality cross-sectional imaging 1,2 .A weighted incidence of incidental pancreatic cysts of up to 49% has been reported in the general population 3 .The most common pancreatic cystic neoplasm is intraductal pancreatic mucinous neoplasm (IPMN), for which surveillance is mostly recommended, whereas high-risk patients (for example those with IPMN with mural nodules, jaundice, and main duct dilatation exceeding 10 mm) are recommended to undergo resection to prevent malignant degeneration 4,5 . https://doi.org/10.1093/bjs/znad424

Original Article
Distal pancreatectomy is the standard surgical procedure for IPMN located in the pancreatic body and tail requiring resection.In patients with malignant disease (such as pancreatic cancer), distal pancreatectomy is routinely combined with splenectomy to ensure radical resection of potential lymph node metastases (LNMs).At present, both international 4 and European 5 guidelines recommend distal pancreatectomy with splenectomy for all patients with IPMN requiring distal pancreatectomy.However, the need for distal pancreatectomy with splenectomy in patients with premalignant IPMN remains unclear because this advice is based on small cohort studies, and a possible survival benefit compared with spleen-preserving distal pancreatectomy has never been proven.
Splenectomy has been associated with an impaired immune response, need for immunization, and a 0.1-8.5% risk of a potentially lethal overwhelming postsplenectomy infection (OPSI) 6 .Furthermore, long-term follow-up studies in American veterans 7,8 have shown an increased risk of death from pneumonia, ischaemic heart disease, septicaemia, pulmonary embolism, and different types of cancer, even more than 10 years after splenectomy.Patients with resected IPMN have an excellent prognosis (pooled 5-year survival rate 93.6% in 2868 patients) 9 and could therefore benefit from spleen preservation.In general, spleen-preserving distal pancreatectomy has been associated with less blood loss, shorter hospital stay and improved long-term health outcomes compared with distal pancreatectomy with splenectomy 10,11 .
This study aimed to assess the oncological and surgical outcomes of spleen-preserving distal pancreatectomy and distal pancreatectomy with splenectomy in patients with presumed IPMN with and without suspected malignancy in a large, international, multicentre cohort.The primary outcome was the rate of LNM.Secondary outcomes included overall survival (OS), duration of operation, estimated blood loss, and need for secondary splenectomy.

Study design
This was an international, multicentre retrospective cohort study that included centres participating in the Verona Evidence Based Medicine (EBM) 2020 IPMN consortium.The present manuscript was redacted and drafted under the auspices of this consortium 12 .Patients were included from 14 high-volume centres (defined by at least 15 distal pancreatectomies per year for all indications) in 7 countries, which all performed distal pancreatectomy with splenectomy and spleen-preserving distal pancreatectomy.This study was conducted in accordance with the STROBE guidelines for reporting observational studies 13 .The study protocol was approved by the institutional review board of Amsterdam UMC and the requirement to obtain informed consent was waived.All participating institutions followed local regulations regarding study approval and informed consent procedures.

Study population
Consecutive patients who had undergone distal pancreatectomy, either spleen-preserving distal pancreatectomy or distal pancreatectomy with splenectomy, for presumed IPMN between 1 January 2005 and 31 December 2019 were eligible for inclusion.For spleen-preserving distal pancreatectomy, both the Warshaw procedure (splenic vessel resecting) 14 and the Kimura procedure (splenic vessel preserving) 15 were included.Planned distal pancreatectomy with splenectomy included patients in whom splenectomy was planned before operation, thereby excluding emergency splenectomies.Patients were excluded if essential information was lacking (surgical or pathology reports missing) or if pancreatic resections other than distal pancreatectomy were performed.The diagnosis of IPMN was based on the preoperative assessment by the local multidisciplinary team.Subgroup analyses were undertaken for patients with and without preoperative suspicion of malignancy.Patients were classified as having suspected malignancy if there was preoperative suspicion of a solid mass, cytology showing malignancy, or lymphadenopathy on preoperative imaging.All other patients were classified as not having a suspected malignancy, regardless of the postoperative dysplasia grade.Patients in whom the indication for resection was unknown were omitted from these subgroup analyses.

Data collection
Invitations to participate in the present study were distributed via e-mail through the EBM 2020 on IPMN consortium.After an initial participation survey (Google™ Survey, Mountain View, CA, USA) confirming the study requirements, each participating centre appointed one dedicated local study coordinator, who was responsible for all communication with the central study coordinator.The local study coordinator was responsible for data entry into the electronic case report form using Castor EDC 16 .An overview of the variables collected is available in Table S1.

Outcomes
The primary outcome was the rate of LNM, both overall and in patients with and those without suspected malignancy.Secondary outcomes included duration of operation, estimated blood loss, 90-day pancreas-specific complications, major in-hospital morbidity (Clavien-Dindo grade IIIa or higher) 17 , long-term postoperative morbidity (new-onset diabetes mellitus, exocrine pancreatic insufficiency, and secondary splenectomy), and OS.OS was defined as the interval between the date of surgery and date of death or last follow-up.The definitions of the International Study Group on Pancreatic Surgery were used to score postoperative pancreatic fistula 18 , delayed gastric emptying 19 , chyle leak 20 , and postpancreatectomy haemorrhage 21 .Only grade B/C complications were included.Ischaemic morbidity was defined as an abdominal organ complication caused by surgery-related ischaemia.Lymph node stations were reported according to the Japanese classification of pancreatic cancer 22 .Disease staging was carried out according to the seventh version of the AJCC TNM classification 23 until 2017; the eighth version of the AJCC 24 was used from 2018 onwards.

Statistical analysis
Categorical data are presented as numbers with percentages, and were analysed using the χ 2 test or Fisher's exact test, if appropriate.Continuous data are presented as median (i.q.r.) and were compared using the Mann-Whitney U test.OS was calculated using the Kaplan-Meier method and analysed using the log rank test.
All P values were based on a two-sided test and P < 0.050 was considered statistically significant.Data were analysed with the use of SPSS ® Statistics for Windows ® version 26.0 (IBM, Armonk, NY, USA).

Intention-to-treat analysis
Intention-to-treat analysis of the subgroup of patients with a preoperative suspicion of malignancy yielded comparable results (Table S4).In intention-to-treat analysis of patients without suspected malignancy, similar results were observed (Table S5).

Discussion
In this first international cohort study of the role of splenectomy in patients undergoing distal pancreatectomy for IPMN, the LNM rate was 6.7% in the total cohort and 4.3% among patients without a preoperative suspicion of malignancy.Spleen-preserving distal pancreatectomy was associated with a shorter operating time, shorter hospital stay, and less blood loss than distal pancreatectomy with splenectomy, and comparable OS.The 6.7% rate of LNM after distal pancreatectomy observed here cannot be compared with findings of previous studies as these combined all types of pancreatectomy for IPMN.In a single-year analysis 25 in over 100 US centres, 21 patients (4.4%) had LNM among 478 patients after any type of pancreatectomy for IPMN.A single-centre series 26 from Johns Hopkins identified 183 patients (29.7%) with malignancy and 97 (15.7%) with LNM among 616 patients undergoing any type of pancreatectomy for IPMN.Two smaller single-centre studies 27,28 reported LNM in 7 of 98 (7%) and 27 of 244 (11.1%) patients undergoing any type of pancreatectomy for IPMN respectively.
The main benefit of spleen-preserving distal pancreatectomy is improvement in short-term outcome and preservation of splenic function, which may be considered especially important as most patients with IPMN have a very good life expectancy; however, the proportion of minimally invasive operations was higher in the  Values in parentheses are 95% confidence intervals.*New onset or worsening of pre-existing diabetes mellitus, pancreatitis, or persisting abdominal symptoms.SPDP, spleen-preserving distal pancreatectomy; CA19.9, carbohydrate antigen 19.9.
spleen-preserving distal pancreatectomy group (Table S6), and so the results should be interpreted with caution.A 2014 meta-analysis 10 compared outcomes after spleen-preserving distal pancreatectomy and distal pancreatectomy with splenectomy in 879 patients for all indications, and concluded that spleen-preserving distal pancreatectomy was associated with a shorter hospital stay (weighted mean difference 1.16, 95% c.i. −2.00 to −0.31; P = 0.007) and fewer intra-abdominal abscesses (OR 0.48, 0.27 to 0.83; P = 0.009), whereas other outcomes did not differ (such as blood loss and duration of operation).A more recent study 29 reported high success rates (80%) for laparoscopic spleen-preserving distal pancreatectomy in 229 patients with benign and low-grade malignant disease, with no differences in postoperative morbidity in propensity score-matched patients, compared with 227 patients who underwent distal pancreatectomy with splenectomy.The authors concluded that spleen-preserving distal pancreatectomy is preferred for benign or low-grade malignant lesions owing to the increased risk of long-term complications after distal pancreatectomy with splenectomy.
Another recent study 30 of propensity score-matched patients (35 in each group) undergoing distal pancreatectomy for all indications found that the operating time was shorter for laparoscopic spleen-preserving distal pancreatectomy than for laparoscopic distal pancreatectomy with splenectomy.Furthermore, the authors noted higher quality-of-life (QoL) scores after spleen-preserving distal pancreatectomy, albeit the difference was not statistically significant.A follow-up study 31 of 160 patients with benign or low-grade malignant disease reported improved QoL (less fatigue, symptoms of flu and cold, and better health condition) after spleen-preserving distal pancreatectomy versus distal pancreatectomy with splenectomy.
A possible disadvantage of spleen-preserving distal pancreatectomy is the risk of splenic infarction and splenic abscesses.Splenic infarction requiring reoperation was not observed in the present cohort, but other studies reported incidences ranging from 1.9 to 7.3% [31][32][33] .Long-term complications after spleen-preserving distal pancreatectomy according to Warshaw include left-sided portal hypertension and subsequent formation of epigastric varices.Unfortunately, these were not registered in the authors' database and so it was not possible to provide data on this complication.Two of the aforementioned studies 31,32 with long-term follow-up reported a 9 and 25% risk of varices after spleen-preserving distal pancreatectomy according to Warshaw in 65 and 111 patients respectively, although no significant gastrointestinal bleeding was observed.
Focusing on OS, the good life expectancy (90% after a median follow-up of 4.6 years) observed here is in accordance with a systematic review 9 from 2016, in which the pooled 5-year survival rate in 2868 patients was 93.6% (95% c.i. 90.5 to 95.7).A more recently published abstract 34 with 10-year nationwide follow-up of 88 resections (all types) for IPMN reported a 5-year survival rate of 87.5% for patients with low-grade dysplasia, 77.8% for those with high-grade dysplasia, and 35.9% for patients with invasive IPMN.
The present data suggest that spleen-preserving distal pancreatectomy was safe in patients with IPMN without preoperative suspicion of malignancy selected for this approach.According to the current policies for IPMN resection, most resected IPMNs do not harbour either high-grade dysplasia or invasive cancer 35,36 .Ultimately, a large pragmatic randomized trial should confirm the non-inferiority of spleen-preserving distal pancreatectomy to distal pancreatectomy with splenectomy for patients with IPMN without suspected malignancy.Such a study should include long-term follow-up to create insight into the long-term complications of both spleen-preserving distal pancreatectomy (for example varices) and distal pancreatectomy with splenectomy (such as OPSI), and should also include QoL questionnaires.In addition, standardization of lymph node station reporting is needed to distinguish LNMs accurately.If the results of these future studies show that spleen-preserving distal pancreatectomy has significant benefit over distal pancreatectomy with splenectomy in patients with IPMN, spleen-preserving distal pancreatectomy might be implemented in clinical practice, thus potentially improving surgical outcomes and QoL.In the present study, 5 of 106 patients had invasive cancer in the spleen-preserving distal pancreatectomy group but none underwent secondary splenectomy.The clinical consideration remains open for debate whether a secondary splenectomy should be performed.
The results of this study should be interpreted considering several limitations.First, owing to the retrospective design, the results are subject to indication bias.This is reflected by the higher dysplasia grade and higher rate of LNM in patients undergoing distal pancreatectomy with splenectomy for IPMN, indicating that patients with higher preoperative risk were specifically selected for distal pancreatectomy with splenectomy.Nevertheless, this was corrected for in Cox regression analyses.Second, it was not possible to provide detailed data on the location of LNMs (splenic hilum versus elsewhere) because this information was not present in most pathology reports.Additionally, stage migration might have taken place as a median of 11 (i.q.r.5-20) lymph nodes were harvested per patient.Third, long-term follow-up was lacking in some patients, and the reliability of detection of the consequences of spleen-preserving distal pancreatectomy and distal pancreatectomy with splenectomy (for example OPSI) might therefore have been impaired.Fourth, data were not collected on IPMN recurrence.Fifth, the inclusion period of 15 years might have led to confounding because guidelines have changed over this interval, pancreatic cystic neoplasms are increasingly being diagnosed, and use of the minimally invasive approach has increased.The main strength of this study is its multicentre, international design with a considerable cohort of patients undergoing distal pancreatectomy for presumed IPMN.This study is also the first to provide insight into OS between patients undergoing spleen-preserving and those having distal pancreatectomy with splenectomy for IPMN.A future pragmatic randomized trial should confirm the non-inferiority of spleen-preserving distal pancreatectomy compared with distal pancreatectomy with splenectomy in patients requiring distal pancreatectomy for presumed IPMN without suspected malignancy.